The present application relates to the identification and isolation of a gene which is responsible for the adrenoleukodystrophy. It further concerns the protein encoded by this gene and their use in diagnostic or therapeutic procedures.
Adrenoleukodystrophy (ALD) is an X-linked disease affecting 1/20,000 males either as cerebral ALD in childhood or as adrenomyleneuropathy (AMN) in adults. Childhood ALD is the more severe form, with onset of neurological symptoms between 5-12 years of age. Central nervous system demyelination progresses rapidly and death occurs within a few years. AMN is a milder form of the disease with onset at 15-30 years of age and a more progressive course. Adrenal insufficiency (Addison's disease) may remain the only clinical manifestation of ALD. The principal biochemical abnormality of ALD is the accumulation of very long chain fatty acids (VLCFA) because of impaired .beta.-oxidation in peroxisomes. The normal oxidation of VLCFA-CoA in patients fibroblasts suggested that the gene coding for the VLCFA-CoA synthetase could be a candidate gene for ALD.
ALD or its variant AMN is a monogenic disease but its clinical expression can be under the control of several genes or factors, leading to phenotypic variability.
Adrenoleukodystrophy and adrenomyeloneuropathy are characterized by the presence of an abnormal ALD gene, resulting from deletions or other types of mutations including point mutations. The mutations in the gene may nevertheless remain clinically silent or may lead to various phenotypic clinical expression.
Although it was known that the gene responsible for the adrenoleukodystrophy is located on the Xq28 region of the X chromosome, the results which have been described up to now have not permitted to identify and characterize the gene responsible for the ALD.
Some experiments were for instance conducted in order to check any possible relationship between the alteration of the gene responsible for the colour vision and the ALD gene. The inventors have now shown that although these genes of the red/green colour pigment also map to the Xq28 region, they are not linked either structurally or functionally to the ALD gene.
For the purpose of this description, it is mentioned that the expression "ALD gene" encompasses the gene involved in ALD and also in its adult variant AMN.